PubMed · 9935312
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
S P East. 1998. Combing the web.. https://doi.org/10.1016/s1074-5521(98)90669-x
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
The ability of supercritical water (SCW) to decompose heterocyclic compounds (quinoline and isoquinoline) has been explored in this study. The results obtained suggest that water acts as a chemical reagent above its critical point (374 degrees C and 22.1 MPa). Significant proportions of isoquinoline and quinoline were removed during the reaction with SCW. The response of these compounds to pyrolysis was also compared with their reaction with SCW. Both compounds were relatively more reactive in the presence of SCW than during pyrolysis. Because of the different positions of N atom in the two compounds, they reacted with SCW differently. Breaking of C-N bonds during SCW reaction was by hydrogenation and hydrocracking, while pyrolysis was due to thermocracking mainly.
A model of molecular diversity is presented. The model, termed "Quantized Surface Complementarity Diversity" (QSCD), defines molecular diversity by measuring molecular complementarity to a fully enumerated set of theoretical target surfaces. Molecular diversity space is defined as the molecular complement to this set of enumerated surfaces. Using a set of known test compounds, the model is shown to be biologically relevant, consistently scoring known actives as similar. At the resolution of the model, which examines molecules "quantized" into 4.24 A cubic units and treats four points of specific energetic complementarity, the minimum number of compounds needed to fully cover molecular diversity space up to volume 1070 cubic A is estimated to be on the order of 24 million molecules. Most importantly, QSCD allows for individual points in diversity space to be filled by direct modeling of molecular libraries into detailed 3D templates of shape and functionality.
In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.